The understanding of autoimmune thyroid diseases, Hashimoto's thyroiditis and Graves disease (GD), remains superficial and current treatment is symptom-oriented. The mediators responsible for the lymphocytic infiltration and inflammation characteristic of autoimmune thyroid glands have not been identified. The long-term objective of this project is to investigate the role of thyroid epithelial cells in the inflammatory response. Here, we propose experiments designed to 1) investigate the pathogenesis of thyroid inflammation 2) identify potential therapeutic targets for interrupting these processes and 3) identify clinical markers of autoimmune thyroid disease activity. Cellular immunology, protein chemistry and molecular biology techniques will be utilized to examine thyrocyte expression of immunomodulatory molecules in vitro and in situ. We propose to measure serum levels of inflammatory mediators and attempt to correlate their serum levels with disease activity in a 48-month prospective study of patients with Graves' disease. The candidate and mentor have worked closely for over 3 years. This relationship has led to significant production and the generation of supporting preliminary data. With the support of a research career development award, continued mentoring and the availability of a General Clinical Research Center, the candidate will be able to further investigate his findings and answer the clinically relevant questions that have arisen. During the career development period, the candidate will also complete graduate level coursework in molecular biology and translational investigation. The candidate will develop the scientific knowledge base, problem solving abilities, and technical skills which will allow him to develop into a independent physician/scientiist.